Anti-prlr antibody-drug conjugates (adc) and uses thereof

Abstract

Provided are antibody drug conjugates that bind PRLR, in particular human PRLR, their methods of making, and uses thereof.

1 - 11 . (canceled) 
     
     
         12 . An antibody-drug conjugate (ADC) comprising the structure of Formula (IX), or a salt thereof 
       
         
           
           
               
               
           
         
         wherein Formula (IX) comprises a monoclonal anti-PRLR antibody (Ab) conjugated to at least one cytotoxic warhead, 
         wherein D comprises a pyrrolobenzodiazepine (PBD) dimer; Y is Val, Z is Ala, and q is 1, 2, 3, 4, 5, 6, 7, or 8, and wherein said monoclonal anti-PRLR antibody comprises: 
         i. a heavy chain variable region comprising a CDRH1 sequence comprising SEQ ID NO: 3, a CDRH2 sequence comprising SEQ ID NO: 4, and a CDRH3 sequence comprising SEQ ID NO: 5; 
         ii. a light chain variable region comprising a CDRL1 sequence comprising SEQ ID NO: 8, a CDRL2 sequence comprising SEQ ID NO: 9, and a CDRL3 sequence comprising SEQ ID NO: 10; and 
         iii. a mutation comprising S239C in a heavy chain constant region, wherein the numbering is in accordance with Kabat, and 
         wherein said monoclonal anti-PRLR antibody is conjugated to said at least one cytotoxic warhead through said S239C mutation in said heavy chain constant region. 
       
     
     
         13 . The ADC of  claim 12 , wherein q is 5. 
     
     
         14 - 15 . (canceled) 
     
     
         16 . The ADC of  claim 12 , wherein said monoclonal anti-PRLR antibody comprises an IgG1 isotype. 
     
     
         17 . The ADC of  claim 12 , wherein said heavy chain constant region of said monoclonal anti-PRLR antibody either lacks a C-terminal lysine or comprises an amino acid other than lysine at a C-terminus of the heavy chain constant region. 
     
     
         18 . The ADC of  claim 12 , wherein said monoclonal anti-PRLR antibody is a humanized antibody. 
     
     
         19 . The ADC of  claim 12 , wherein said ADC has a drug load of two cytotoxic warheads per anti-PRLR antibody. 
     
     
         20 . The ADC of  claim 13 , wherein said monoclonal antibody comprises an IgG1 isotype. 
     
     
         21 . The ADC of  claim 13 , wherein said heavy chain constant region of said monoclonal anti-PRLR antibody either lacks a C-terminal lysine or comprises an amino acid other than lysine at a C-terminus of the heavy chain constant region. 
     
     
         22 . The ADC of  claim 13 , wherein said monoclonal anti-PRLR antibody is a humanized antibody. 
     
     
         23 . The ADC of  claim 13 , wherein said ADC has a drug load of two cytotoxic warheads per anti-PRLR antibody. 
     
     
         24 . An antibody-drug conjugate (ADC) comprising the structure of Formula (IX), or a salt thereof, 
       
         
           
           
               
               
           
         
         wherein Formula (IX) comprises a monoclonal anti-PRLR antibody (Ab) conjugated to at least one cytotoxic warhead, 
         wherein D comprises a pyrrolobenzodiazepine (PBD) dimer; Y is Val, Z is Ala, and q is 1, 2, 3, 4, 5, 6, 7, or 8, and wherein said monoclonal anti-PRLR antibody comprises: 
         i. a heavy chain variable region comprising SEQ ID NO: 2; 
         ii. a light chain variable region comprising SEQ ID NO: 7; and 
         iii. a mutation comprising S239C in a heavy chain constant region, wherein the numbering is in accordance with Kabat, and 
         wherein said monoclonal anti-PRLR antibody is conjugated to said at least one cytotoxic warhead through said S239C mutation in said heavy chain constant region. 
       
     
     
         25 . The ADC of  claim 24 , wherein q is 5. 
     
     
         26 . The ADC of  claim 24 , wherein said monoclonal antibody comprises an IgG1 isotype. 
     
     
         27 . The ADC of  claim 24 , wherein said heavy chain constant region of said monoclonal anti-PRLR antibody either lacks a C-terminal lysine or comprises an amino acid other than lysine at a C-terminus of the heavy chain constant region. 
     
     
         28 . The ADC of  claim 24 , wherein said monoclonal anti-PRLR antibody is a humanized antibody. 
     
     
         29 . The ADC of  claim 24 , wherein said ADC has a drug load of two cytotoxic warheads per anti-PRLR antibody. 
     
     
         30 . The ADC of  claim 25 , wherein said monoclonal antibody comprises an IgG1 isotype. 
     
     
         31 . The ADC of  claim 25 , wherein said heavy chain constant region of said monoclonal anti-PRLR antibody either lacks a C-terminal lysine or comprises an amino acid other than lysine at a C-terminus of the heavy chain constant region. 
     
     
         32 . The ADC of  claim 25 , wherein said monoclonal anti-PRLR antibody is a humanized antibody. 
     
     
         33 . The ADC of  claim 25 , wherein said ADC has a drug load of two cytotoxic warheads per anti-PRLR antibody. 
     
     
         34 . An antibody-drug conjugate (ADC) comprising the structure of Formula (IX), or a salt thereof, 
       
         
           
           
               
               
           
         
         wherein Formula (IX) comprises a monoclonal anti-PRLR antibody (Ab) conjugated to at least one cytotoxic warhead, 
         wherein D comprises a pyrrolobenzodiazepine (PBD) dimer; Y is Val, Z is Ala, and q is 1, 2, 3, 4, 5, 6, 7, or 8, and wherein said monoclonal anti-PRLR antibody comprises: 
         i. a full heavy chain comprising SEQ ID NO: 1; and 
         ii. a full light chain comprising SEQ ID NO: 6; 
         wherein said monoclonal anti-PRLR antibody is conjugated to said at least one cytotoxic warhead through amino acid residue 242 of SEQ ID NO: 1. 
       
     
     
         35 . The ADC of  claim 34 , wherein q is 5. 
     
     
         36 . The ADC of  claim 34 , wherein said heavy chain constant region of said monoclonal anti-PRLR antibody either lacks a C-terminal lysine or comprises an amino acid other than lysine at a C-terminus of the heavy chain constant region. 
     
     
         37 . The ADC of  claim 34 , wherein said ADC has a drug load of two cytotoxic warheads per anti-PRLR antibody. 
     
     
         38 . The ADC of  claim 35 , wherein said heavy chain constant region of said monoclonal anti-PRLR antibody either lacks a C-terminal lysine or comprises an amino acid other than lysine at a C-terminus of the heavy chain constant region. 
     
     
         39 . The ADC of  claim 35 , wherein said ADC has a drug load of two cytotoxic warheads per anti-PRLR antibody. 
     
     
         40 . An antibody-drug conjugate (ADC) comprising the structure of Formula (IX), 
       
         
           
           
               
               
           
         
         wherein Formula (IX) comprises a monoclonal anti-PRLR antibody (Ab) conjugated to a cytotoxic warhead, 
         wherein D comprises a pyrrolobenzodiazepine (PBD) dimer; Y is Val, Z is Ala, and q is 5 and wherein said monoclonal anti-PRLR antibody comprises: 
         i. a heavy chain variable region comprising a CDRH1 sequence comprising SEQ ID NO: 3, a CDRH2 sequence comprising SEQ ID NO: 4, and a CDRH3 sequence comprising SEQ ID NO: 5; 
         ii. a light chain variable region comprising a CDRL1 sequence comprising SEQ ID NO: 8, a CDRL2 sequence comprising SEQ ID NO: 9, and a CDRL3 sequence comprising SEQ ID NO: 10; and 
         iii. a mutation comprising S239C in a heavy chain constant region, wherein the numbering is in accordance with Kabat, 
         wherein said monoclonal anti-PRLR antibody is conjugated to said cytotoxic warhead through said S239C mutation in said heavy chain constant region, and 
         wherein said ADC has a drug load of two cytotoxic warheads per anti-PRLR antibody. 
       
     
     
         41 . The ADC of  claim 40 , wherein said monoclonal antibody comprises an IgG1 isotype. 
     
     
         42 . The ADC of  claim 40 , wherein said heavy chain constant region of said monoclonal anti-PRLR antibody either lacks a C-terminal lysine or comprises an amino acid other than lysine at a C-terminus of the heavy chain constant region. 
     
     
         43 . The ADC of  claim 40 , wherein said monoclonal anti-PRLR antibody is a humanized antibody. 
     
     
         44 . An antibody-drug conjugate (ADC) comprising the structure of Formula (IX), 
       
         
           
           
               
               
           
         
         wherein Formula (IX) comprises a monoclonal anti-PRLR antibody (Ab) conjugated to a cytotoxic warhead, 
         wherein D comprises a pyrrolobenzodiazepine (PBD) dimer; Y is Val, Z is Ala, and q is 5 and wherein said monoclonal anti-PRLR antibody comprises: 
         i. a heavy chain variable region comprising SEQ ID NO: 2; 
         ii. a light chain variable region comprising SEQ ID NO: 7; and 
         iii. a mutation comprising S239C in a heavy chain constant region, wherein the numbering is in accordance with Kabat, 
         wherein said monoclonal anti-PRLR antibody is conjugated to said cytotoxic warhead through said S239C mutation in said heavy chain constant region, and 
         wherein said ADC has a drug load of two cytotoxic warheads per anti-PRLR antibody. 
       
     
     
         45 . The ADC of  claim 44 , wherein said monoclonal antibody comprises an IgG1 isotype. 
     
     
         46 . The ADC of  claim 44 , wherein said heavy chain constant region of said monoclonal anti-PRLR antibody either lacks a C-terminal lysine or comprises an amino acid other than lysine at a C-terminus of the heavy chain constant region. 
     
     
         47 . The ADC of  claim 44 , wherein said monoclonal anti-PRLR antibody is a humanized antibody. 
     
     
         48 . An antibody-drug conjugate (ADC) comprising the structure of Formula (IX), 
       
         
           
           
               
               
           
         
         wherein Formula (IX) comprises a monoclonal anti-PRLR antibody (Ab) conjugated to a cytotoxic warhead, 
         wherein D comprises a pyrrolobenzodiazepine (PBD) dimer; Y is Val, Z is Ala, and q is 5, and wherein said monoclonal anti-PRLR antibody comprises: 
         i. a full heavy chain comprising SEQ ID NO: 1; and 
         ii. a full light chain comprising SEQ ID NO: 6; 
         wherein said monoclonal anti-PRLR antibody is conjugated to said cytotoxic warhead through amino acid residue 242 of SEQ ID NO: 1, and 
         wherein said ADC has a drug load of two cytotoxic warheads per anti-PRLR antibody. 
       
     
     
         49 . The ADC of  claim 48 , wherein said heavy chain constant region of said monoclonal anti-PRLR antibody either lacks a C-terminal lysine or comprises an amino acid other than lysine at a C-terminus of the heavy chain constant region.